This proposal is designed to describe the alteration of alpha-adrenergic sensitivity that occurs in the peripheral vasculature during normal pregnancy and with short-term steroid hormone treatment. It will also assess some of the mechanisms responsible for these alterations. Using pregnant and nonpregnant ewes, I will examine the local vascular reactivity to various alpha-adrenergic agonists in a chronic skeletal muscle and superior mesenteric artery preparations, and in small skeletal and mesenteric arteries in a specially designed in-vitro myograph system. In addition, we will utilize radioligand techniques in order to study the alpha and beta-adrenergic receptors on the vascular smooth muscle from the same tissue. In the chronic models, blood flow and vascular resistance changes will be measured in response to norepinephrine, epinephrine, methoxamine and phenylephrine in ovariectomized, ovariectomized-progesterone and estrogen-progesterone treated, and pregnant ewes. The relative positions of these dose response curves will allow us to begin to evaluate the contribution that intraneuronal and extraneuronal uptake and metabolism make towards sensitivity changes to alpha-adrenergic stimulation in these vascular beds. We will verify the in-vivo work by an in-vitro analysis of these same drugs, including blockers of intra- and extraneuronal uptakes. In addition, the maximum force generating capability of these vessels will be determined. Finally, the in-vivo and in-vitro pharmacologic information regarding adrenergic sensitivity will be correlated with the biochemical analysis of the adrenergic receptors from the same tissues. The significance of this proposal is that it will correlate accurate in-vitro information about resistance vessels from pregnant and steroid treated animals to the vascular responses which occur in-vivo. It will contribute to our understanding of blood pressure regulation during pregnancy and provide a data base for exploring the hypertensive disorders of pregnancy during which there is an inappropriate cardiovascular adjustment to pregnancy.